tbuckley/cabot-search huggingface dataset:
Characterization of the source(s) of lipocalin-2 mediating dietary obesity-induced hypertension
Authors: D Konja, H Li, B Fu, S Singh, Y Wang
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by the grants from the General Research Funds (17117017 and 17121714) and Collaborative Research Funds (C7037-17W) of Research Grant Council, the Areas of Excellence Scheme (AoE/M-707/18) of University Grants Committee Title: Characterization of the source(s) of lipocalin-2 mediating dietary obesity-induced hypertension. Introduction Obesity upregulates lipocalin-2 (Lcn2), a pro-inflammatory adipokine, which in turn induces vascular and metabolic abnormalities. In mice, deletion of the Lcn2 alleles has protective effects against obesity-induced vascular and metabolic dysfunctions. Purpose The present study investigated the sources of lipocalin-2 production as a mediator of dietary obesity-associated perivascular adipose tissue dysfunction and hypertension. Methods The wild type (WT) littermates or mice with whole body knockout (LKO), adipose tissue (Adn-Cre)-, kidney (Wt1-Cre)-, liver (Alb-Cre)-, and granuloid cells (Lys-Cre)-selective deletion of the Lcn2 alleles were implanted with radio-telemetry transmitters at eight-weeks of age. Blood pressure was recorded at least four 12/12 light-dark cycles every four weeks for mice fed either standard chow (STC) or high fat diet (HFD). Wire myography was performed to evaluate the functional properties of mesenteric arteries, in the presence or absence of surrounding perivascular adipose tissues. Quantitative PCR, Western blotting as well as enzyme-linked immunosorbent assay (ELISA) were also performed to measure Lcn2 expression in tissues and blood respectively. Results Compared to STC, HFD feeding increased systolic, diastolic, mean arterial and pulse pressure in WT mice. The amount of Lcn2 expressed in perivascular adipose tissues and present in blood were also higher in HFD-fed WT mice when compared to those fed with STC. Whole body deletion of Lcn2 alleles attenuated HFD- induced increase in blood pressure. Liver-selective deletion of Lcn2 alleles abolished the effect of HFD feeding on blood pressure, decreased Lcn2 expression in perivascular adipose tissues, and the concentration of Lcn2 in blood. Both whole body- and liver-specific deletion of Lcn2 alleles enhanced the anti-contractile activity of perivascular adipose tissues and abolished HFD-induced adipose tissue dysfunction. However, deletion of Lcn2 alleles selectively in adipose tissues, but not Wt1-Cre and Lys-Cre, partially mitigated the effects of HFD on perivascular adipose tissue function and blood pressure regulation. Conclusion Lcn2 derived from different tissues are distinctively implicated in dietary obesity-induced perivascular adipose tissue dysfunction and hypertension.
Comparing an operation to monitoring, with or without endocrine therapy (COMET), for low-risk ductal carcinoma in situ (DCIS).
Authors: Thomas Lynch, Elizabeth S. Frank, Deborah E. Collyar, Donna Pinto, Desiree Basila, Ann H. Partridge, Alastair Mark Thompson, Eun-Sil Shelley Hwang, Fan Li, Yi Ren, Terry Hyslop
Journal: Journal of Clinical Oncology (2022)

TPS616 Background: Approximately 50,000 women in the U.S. are diagnosed with ductal carcinoma in situ (DCIS) each year. Without treatment, it is estimated that only 20-30% of DCIS will lead to invasive breast cancer (IBC). However, over 97% of women are currently treated with surgery +/- radiation. An alternative to surgery is active monitoring (AM), a management approach in which mammograms/physical exams are used to monitor breast changes and determine when, or if, surgery is needed. The COMET Study will compare risks and benefits of AM versus surgery for low-risk DCIS in the setting of a Phase III multicenter prospective randomized trial. The study is funded by the Patient-Centered Outcomes Research Institute. The COMET trial opened in the U.S. in June 2017 (Clinicaltrials.gov reference: NCT02926911). In November 2021, the Data Safety Monitoring Board reviewed the trial and suggested that it continue as planned. Patient accrual will continue until 12/31/2022. Methods: The primary objective is to assess whether the 2-year ipsilateral IBC rate for AM is non-inferior to that for surgery. Secondary objectives include determining whether AM is non-inferior to surgery for 2-year mastectomy rate; breast conservation rate; contralateral breast cancer rate; overall and breast cancer-specific survival. Patient reported outcomes will enable comparison of health-related quality of life and psychosocial outcomes between surgery and AM groups at baseline, 6-months, and years 1-5. Eligibility criteria include: age &gt; 40 at diagnosis; pathologic confirmation of grade I/II DCIS or atypia verging on DCIS without invasion by two pathologists; ER and/or PR ≥ 10%; no mass on physical exam or imaging. The accrual goal is 1200 randomized patients across 100 Alliance for Clinical Trials in Oncology sites. Sample size is estimated using a 2-group test of non-inferiority of proportions, with the 2-year IBC rate in the surgery group assumed to be 0.10 based on published studies and non-inferiority margin of 0.05. Based on a 1-sided un-pooled z-test, with alpha = 0.05, a sample size of n = 446 per group will have 80% power to detect the specified non-inferiority margin. Final analysis plan will include a per protocol component as well as a pragmatic component for patients who are randomized and decline participation in their assigned arm. Primary analyses will adjust for dropout, non-compliance and contamination by utilizing instrumental variable methods. Clinical trial information: NCT02926911.
Prospective randomized trial assessing the severity of irritative symptoms after Holmium Laser Enucleation of the Prostate (HoLEP) versus Thulium Fiber Laser Enucleation of the Prostate (ThuFLEP)
Authors: D. Enikeev, M. Taratkin, D. Babaevskaya, V. Petov, M. Enikeev, R. Sukhanov, E. Shpot, D. Chinenov, T. Herrmann
Journal: European Urology (2022)
Deep learning in robot-assisted partial nephrectomy: Advent of realistic augmented reality
Authors: P. De Backer, C. Allaeys, H. Creemers, A. Hallemeesch, K. Mestdagh, F. Cisternino, F. Ferraguti, S. Vermijs, R. Janssens, C. Van Praet, J. Dambre, C. Debbaut, K. Decaestecker, A. Mottrie
Journal: European Urology (2022)
Clinical and molecular characterization of fusion genes in colorectal cancer.
Authors: Canan Karan, Elaine Tan, Humaira Sarfraz, Christine Marie Walko, Richard D. Kim, Todd C Knepper, Ibrahim Halil Sahin
Journal: Journal of Clinical Oncology (2022)

e15568 Background: Next-generation sequencing (NGS) based molecular profiling technologies have revealed several oncogenic fusion genes that are actionable with small molecule inhibitors leading to practice change, particularly in lung cancer. The molecular and clinical characteristics of these gene fusions are not well defined in colorectal cancer patients (CRC). In this study, we aimed to define clinical and molecular characteristics of fusion genes in patients with CRC who underwent molecular profiling. Methods: Molecular characteristics of tissue confirmed 917 CRC patients were retrieved from the Moffit Cancer Center Clinical Genomics Action Committee database. Patients’ demographic and clinicopathological features and treatment history were collected from the database. All fusion genes were shown by hybridization-based NGS computational algorithms that determined cancer‐related genes, including single‐nucleotide variations, indels, microsatellite instability (MSI) status. Results: Among a total of 917 patients, 24 patients with CRC (2.6%) were found to have at least one fusion gene with a total number of 26 pathogenic fusions. The gene fusions are shown in Table. The most common, potentially targetable, fusion genes in our cohort were (1) RET fusions 0.5% (5/917), (2) ALK fusions 0.4% (4/917), (3) ROS1 fusions 0.2% (2/917), (4) NTRK1 fusion 0.1% (1/917), (5) NRG1 fusion 0.1% (1/917). Fusion genes were more common in MSI-H CRC (N = 27), and 3 (11.1%) patients with MSI-H CRC were found to have fusion genes [(RET (2) and NTRK(1)]. Fusion genes were present in both RAS wild-type (54%; 13/24) and RAS mutant (46%; 11/24) tumors. Most patients were older than 50 years (75%, 18/24) and had left-sided tumor (61.1%) tumor. Conclusions: Fusion genes are rare events in CRC. While fusion genes seem to be more prevalent in MSI-H CRC, RAS status does not correlate with the frequency of fusion genes. Actionable RET and ALK/ROS gene fusion are more common than NTRK fusion genes in this cohort of CRC patients.[Table: see text]
EPEN-03. USP7 is an interaction partner of EZHIP and potential druggable target in PFA ependymomas
Authors: Anne Jenseit, Aylin Camgöz, Monika Mauermann, Stefan Pfister, Marcel Kool
Journal: Neuro-Oncology (2022)

Abstract Ependymomas (EPN) arise in the supratentorial brain (ST-EPN), posterior fossa (PF-EPN), or the spinal cord (SP-EPN), in children and adults. Molecular profiling has identified distinct subgroups in each location. Among the three molecular subgroups of PF-EPN, PFAs are characterized by young median age at diagnosis, an overall balanced genome and bad clinical outcome (56 % 10-year OS). Therapy involves tumor resection and radiotherapy, but the role of chemo- or targeted therapies remains to be defined. Recently, we and others identified enhancer of zeste inhibiting protein (EZHIP) as potential driver of PFAs. By inhibiting EZH2, catalytic subunit of the polycomb repressive complex 2 (PRC2), EZHIP prevents the distribution of the epigenetic repressor mark H3K27me3. However, since EZHIP does not possess any known enzymatic functions, it does not seem to be the druggable target urgently searched for in PFA. We therefore focused on essential and potentially druggable interactions. Here, we present ubiquitin-specific protease 7 (USP7), a known cancer regulator with multiple inhibitors available, which has been shown to interact with EZHIP in non-PFA cells. We confirmed this interaction in PFA cells by co-immunoprecipitation and mass spectrometry, and showed that the EZHIP-USP7 interaction is independent of EZH2, a separate interactor of both. Functionally, we show that USP7 de-ubiquitinates EZHIP, preventing its degradation and thus stabilizing it. As EZHIP is essential for PFA cell survival, we aim to target EZHIP indirectly by affecting its stability regulation via USP7. Knockdown experiments showed a susceptibility of PFA cells to a USP7 loss, focusing on proliferation, apoptosis, and expressional changes induced by altered USP7 levels. Moreover, USP7 inhibitors highly affected the survival of different PFA cell lines at a low micromolar IC50 in vitro and in vivo treatments of PFA patient-derived xenografts with USP7 inhibitors are ongoing, hopefully helping to improve targeted therapies for PFA ependymoma patients.
Variation in telemedicine usage in gynecologic cancer: Are we widening or narrowing disparities?
Authors: Leslie Andriani, Anna Jo Bodurtha Smith, Rafael Alvarez, Jonathan Heintz, Emily Meichun Ko
Journal: Journal of Clinical Oncology (2022)

1593 Background: Telemedicine rapidly increased with the COVID-19 pandemic and may be a way to reduce care disparities. Our aim was to evaluate sociodemographic (race, insurance), patient, health system, and cancer factors associated with use of telemedicine in gynecologic cancers. Methods: We conducted a retrospective cohort study of patients with documented endometrial or ovarian cancer using the nationwide de-identified electronic health record-derived Flatiron Health data. We used multi-level regression models to analyze the association of telemedicine usage during COVID-19 pandemic (2020-2021) with sociodemographic, patient, health system, and cancer factors overall. Results: Of 13,450 patients with endometrial or ovarian cancer, 14.4 % (95%CI 14.0-16.1) used telemedicine during COVID-19 for their cancer care within the Flatiron Health network. Insurance was not associated with likelihood of telemedicine in any model. Region was significantly associated with telemedicine usage across models with patients living in the Northeast more likely to use telemedicine. Conclusions: In this large cohort study, we found regional disparities across cancer types and oncology settings. Expanding access to telemedicine may improve racial and geographic disparities in gynecologic cancer. [Table: see text]
IMMU-06. Landscape of adaptive immunity of childhood brain cancers
Authors: Itay Raphael, Maria Chikina, Alberto Broniscer, Ian Pollack, Dhivyaa Rajasundaram, Gary Kohanbash
Journal: Neuro-Oncology (2022)

Abstract T lymphocytes have a unique ability to recognize a vast array of antigens prompted by an enormous T cell receptor (TCR) repertoire. Characterization of tumor-infiltrating T cells (TILs) is key to understand MHC-restricted anti-tumor immunity and for developing T cell-centered immunotherapies such as adoptive cell therapy and tumor vaccines. In the current work, we investigated RNA-Seq data from 997 pediatric brain tumor patients and performed a large-scale comprehensive examination of the immunogenomic and TCR landscape of TILs across the entire spectrum of pediatric brain tumors. We show that the relative ratio between T cell diversity (clonality) and T cell abundance within each sample, represented by the clonal expansion index (CEI), is a strong predictor of prognosis both within and between tumor types. Interestingly, we show that CEI was strongly associated with molecular subgroups of medulloblastoma but not with known tumor-genomic features of these subgroups. Investigation of TCR clones recognizing a common recurrent tumor-antigen across patients based on CDR3 homology and characteristics, reveals 9 TCR clusters which are tumor type restricted with defined prognoses and HLA dominance. Using computational immunogenomics and machine learning-based investigations of these clusters yielded novel putative HLA-restricted tumor antigens which could bind and activate the clusters’ specific TCRs. Importantly, our framework grounded the foundations for developing a precision medicine approach of T cell-centered immunotherapies. These findings have major implications for understanding the interplay between T cell and tumor genomic, and for developing new immunotherapies for children with brain tumors.
Acute promyelocytic leukemia: A single institution's experience.
Authors: Joseph Bennett, Tara L. Lin, Priyanka Venkatesh, Heather Jean Male, Kenneth Byrd
Journal: Journal of Clinical Oncology (2022)

e19001 Background: Acute Promyelocytic Leukemia (APL) is highly curable but carries high risk of early morbidity and mortality, including hemostatic abnormalities, differentiation syndrome and infection. Induction regimens include all-trans-retinoic acid (ATRA) to promote promyelocyte differentiation and arsenic trioxide (ATO), with chemotherapy added for high-risk patients. Our objective was to characterize clinical characteristics and complications during APL induction. Methods: Electronic medical records were screened for ATRA, ATO, or idarubicin from 2011-2021. APL induction hospitalization records were reviewed for: demographics, white blood cell (WBC) and platelet count at presentation, fibrinogen at presentation, time to ATRA administration, time to complete remission (CR), infection, thrombohemorrhagic complications, ATO related QT interval prolongation, incidence of and time to differentiation syndrome. Results: 56 patients (pts) (median age 50) were analyzed. Mean time from initial presentation at our institution to ATRA administration was 1.5 days (range 0-6 days). Findings upon arrival: median WBC 1.7 K/UL (range 0.3-134.9), median platelets 32 K/UL (range 7-373), hypofibrinogenemia in 39.2% (N = 22) (median 161 MG/DL, range 35-473). 80.3% had documented thrombohemorrhagic complications during induction hospitalization: DIC (N = 24), venous thromboembolism (N = 12), gastrointestinal bleed (N = 6), oral mucosal bleeding (N = 5), vaginal bleeding (N = 3), gross hematuria (N = 3), intracranial hemorrhage (N = 3), epistaxis (N = 2), intraocular hemorrhage (N = 1), cerebral vascular accident (CVA) (N = 1). 21% (N = 12) developed differentiation syndrome with mean time of onset of 8.8 days (range 1-23 days). 55% (N = 31) had clinically significant infections most commonly neutropenic fever (N = 13), bacterial pneumonia (N = 10), skin (N = 5) and bacteremia (N = 5). 48 pts were given ATO during induction and 31% (N = 15) developed QT interval prolongation with no arrhythmias in the cohort. Among 8 pts who did not receive ATO, one died prior to therapy initiation and 7 were treated prior to ATO as standard of care. Among evaluable patients (N = 51): 98% (N = 50) achieved complete remission (CR) or complete remission with incomplete count recovery (CRi). Median time to CR was 35 days (range 27-50). 6 pts did not achieve CR or had unknown status: 1 patient died during induction (CVA) and 5 had post-induction bone marrow evaluations at outside facilities. Conclusions: Thrombohemorrhagic complications, infection and differentiation syndrome are critical to be mindful of during the early phase of treatment in APL. Our data adds to the landscape of knowledge regarding the incidence and timeline of complications. Although we observed prolonged QTc in pts on ATO, there were no arrhythmias detected and all pts were able to quickly resume therapy.
Recombination Landscape Divergence Between Populations is Marked by Larger Low-Recombining Regions in Domesticated Rye
Authors: Mona Schreiber, Yixuan Gao, Natalie Koch, Joerg Fuchs, Stefan Heckmann, Axel Himmelbach, Andreas Börner, Hakan Özkan, Andreas Maurer, Nils Stein, Martin Mascher, Steven Dreissig
Journal: Molecular Biology and Evolution (2022)

Abstract The genomic landscape of recombination plays an essential role in evolution. Patterns of recombination are highly variable along chromosomes, between sexes, individuals, populations, and species. In many eukaryotes, recombination rates are elevated in sub-telomeric regions and drastically reduced near centromeres, resulting in large low-recombining (LR) regions. The processes of recombination are influenced by genetic factors, such as different alleles of genes involved in meiosis and chromatin structure, as well as external environmental stimuli like temperature and overall stress. In this work, we focused on the genomic landscapes of recombination in a collection of 916 rye (Secale cereale) individuals. By analyzing population structure among individuals of different domestication status and geographic origin, we detected high levels of admixture, reflecting the reproductive biology of a self-incompatible, wind-pollinating grass species. We then analyzed patterns of recombination in overlapping subpopulations, which revealed substantial variation in the physical size of LR regions, with a tendency for larger LR regions in domesticated subpopulations. Genome-wide association scans (GWAS) for LR region size revealed a major quantitative-trait-locus (QTL) at which, among 18 annotated genes, an ortholog of histone H4 acetyltransferase ESA1 was located. Rye individuals belonging to domesticated subpopulations showed increased synaptonemal complex length, but no difference in crossover frequency, indicating that only the recombination landscape is different. Furthermore, the genomic region harboring rye ScESA1 showed moderate patterns of selection in domesticated subpopulations, suggesting that larger LR regions were indirectly selected during domestication to achieve more homogeneous populations for agricultural use.
Phase 3 VERACITY clinical study of sabizabulin in men with metastatic castration-resistant prostate cancer who have progressed on an androgen receptor targeting agent.
Authors: Robert Dreicer, Franklin Chu, David J Cahn, Robert H. Getzenberg, Domingo Rodriguez, K. Gary Barnette, Mitchell S. Steiner, Daniel R. Saltzstein, Ronald F. Tutrone, Neal D. Shore
Journal: Journal of Clinical Oncology (2022)

TPS5102 Background: Sabizabulin is a first-in-class, oral agent that inhibits microtubule polymerization disrupting the cytoskeleton and arresting cellular proliferation. A Phase 1b/2 clinical study was conducted to establish the MTD and evaluate the preliminary efficacy in men with metastatic castrate resistant prostate cancer (mCRPC) who progressed on at least one androgen receptor targeting agent (ARTA). The most common AEs reported were mild to moderate diarrhea, fatigue, nausea, and vomiting with no clinically relevant neurotoxicity or neutropenia. In the Phase 1b/2, the median radiographic progression free survival for the 63mg dose (n = 55) was 11.4 months (range 6-36+ months) in the Phase 1b portion including responses &gt; 2.75 years. The Phase 3 reformulation which had improved bioavailability is 32mg PO qd. Methods: VERACITY is an ongoing Phase 3 multicenter, randomized, active-control study designed to evaluate sabizabulin in the treatment of mCRPC who have progressed on at least one ARTA. Patients on the study will be chemotherapy naive. Subjects (n = 245) are being randomized in a 2:1 ratio to receive sabizabulin (32 mg/d oral) or active control (alternative ARTA) and will remain on study until radiographic progression-free survival (rPFS). Randomization will be stratified by: measurable disease vs bone-only disease and by prior exposure to ARTA (progressed on one vs more than one prior ARTA). The primary efficacy endpoint of the study is median rPFS. Secondary endpoints include: objective response rate (ORR), duration of objective response, overall survival and time to intravenous (IV) chemotherapy. The Phase 3, VERACITY registration clinical trial is current ongoing in approximately 45 clinical sites with enrollment anticipated to be completed in 2022 and with unblinded results presented in 2023 Based upon the Phase 1b/2 clinical trial, sabizabulin daily chronic oral dosing has a favorable safety profile, is feasible to administer chronically, and has significant and durable antitumor activity. mCRPC that has progressed following ARTAs and prior to taxane chemotherapy, remains an urgent unmet medical need for patients with advanced disease. Sabizabulin is an exciting first-in-class agent that may add to the armamentarium for the treatment of mCRPC following progression on ARTA’s. Clinical trial information: NCT04844749.